L-NAME Potentiates Endothelin-Stimulated Thromboxane Release from Guinea Pig Lung

The bronchoconstrictor response after systemic administration of endothelins (ETs) in the guinea pig is indirectly mediated by thromboxane A 2 (TxA 2 ) release through ET B receptor activation. ETs also trigger the release of nitric oxide (NO) in endothelial cells by activation of ET B receptors. A growing body of evidence indicates that endogenous NO plays a key role in the regulation of pulmonary function. In this study we investigated the effect of an NO synthase inhibitor, L-NAME, on the release of TxA 2 from the isolated, perfused guinea pig lung induced either by ET-1, the selective ET B receptor agonist IRL-1620, bradykinin (BK), or a TXA 2 -mimetic, U 46619. A 30 min intra-arterial (i.a.) infusion of L-NAME (300 μM) potentiated the TxA 2 release with ET-1, IRL 1620, and BK (5, 50, and 50 nM, respectively) infused for 3 min (i.a.). U 46619 (10 nM) was ineffective as a stimulant of pulmonary eicosanoid release. Interestingly, L-NAME did not potentiate the release of prostacyclin (PGI 2 ) triggered by ET-1, IRL 1620, or BK. Our results suggest a predominant role of ET B receptor activation in the release of TXA 2 . Furthermore, we suggest that NO in the guinea pig lung is a potent modulator of the TXA 2 releasing activity of ET-I, IRL 1620, and BK, three agonists known to stimulate the release of NO.